The present invention is directed to substituted sulfonamides and related compounds of the formula I, depicted below, which by inhibiting 5-lipoxygenase enzyme and/or blocking leukotriene receptors, are useful in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardiaI infarction, stroke, irritable bowel disease and related disease states in mammals. The present invention is also directed to pharmaceutical compositions of, and a method of treatment using said compounds of formula (I).
It is known that leukotrienes are compounds produced in mammals by the metabolism of arachidonic acid. Arachidonic acid is metabolized in mammals by means of two distinct pathways, one leading to prostaglandins and thromboxanes, and the other to several oxidative products known as leukotrienes, which are designated by letter-number combinations such as leukotriene B4 (LTB4), leukotriene C4 (LTC4) and leukotriene D4 (LTD4). The first step in this oxidative pathway is the oxidation of arachidonic acid under the influence of 5-lipoxygenase enzyme, an enzyme which is generally inhibited by the compounds of the present invention, thus blocking the synthesis of all leukotrienes. That in itself provides the mechanism sufficient for the utility of these compounds in the treatment or prevention of asthma (where LTC4 and LTD4 are understood to be mediators), arthritis (where LTB4 is understood to be a mediator), psoriasis (where LTB4 is understood to be a mediator), ulcers (where LTC4 and LTD4 are understood to be mediators), myocardial infarction (where LTB4 is understood to be a mediator), stroke (where LTD4 is understood to be a mediator) and irritable bowel disease (where LTB4 is understood to be a mediator). Supplementing this enzyme inhibitory activity is the general ability of the present compounds to antagonize (i.e., to block receptors of) LTB4, LTC4, LTD4 and LTE4. For a review concerning leukotrienes, see Bailey et al., Ann. Reports Med. Chem. 17, pp. 203-217 (1982).
Eggler et al., in PCT Patent Application PCT/US87/02745, describe racemic or optically active substituted tetralins, chromans and related compounds that inhibit 5-lipoxygenase enzyme and antagonize LTB4 and LTD4, and are therefore useful in the prevention and treatment of asthma, arthritis, psoriasis, ulcers, and myocardial infarction.
Kreft et al., in U.S. Pat. No. 4,661,596, describe disubstituted naphthalenes, dihydronaphthalenes and tetralins that inhibit lipoxygenase enzyme and antagonize LTD4, and are therefore useful in the prevention and treatment of asthma.